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PHYSICIANS PERSPECTIVE - Viewpoint based on the following article: Clin Infect Dis 2009;49(1):e1-10

October 2009

Reviewed and edited by:

Lisa Jackson, MD, MPH

Senior Investigator, Group Health Research Institute, Research Professor, Epidemiology, Adjunct Research Professor, Allergy, Infectious Disease and Medicine, University of Washington School of Public Health, Seattle, Washington

Outbreaks of invasive meningococcal disease (IMD) caused by serogroup C meningococcal disease were fairly common in Canada, but since 2001, there has been a significant decline in the incidence of serogroup C disease, partly due to the introduction of meningococcal C conjugate vaccination programs. Serogroup B is responsible for 55% of meningococcal disease nationally, according to a recent Canada Communicable Disease Report, but incidence rates range from approximately 33% in both British Columbia and the Maritimes to 100% in Manitoba (CCDR 2009; 36:ACS-3).

Nationally, serogroup C disease appears to cause approximately one-half of the rest of meningococcal disease in the country, according to the same report; again, however, there is considerable epidemiological variation across the provinces and serogroup C disease rates are either almost identical to or lower than serogroup Y disease rates in some regions.

The National Advisory Committee on Immunization (NACI) also noted that the rates and numbers of serogroup Y meningococcal disease have remained stable over time. Yet on closer examination, the CCDR report indicates that serogroup Y disease accounts for 24% of meningococcal disease in British Columbia, 21% in Alberta, 20% in Saskatchewan and 20% in Ontario (Table 1). Currently, serogroups A and W-135 are responsible for very little IMD across the country.

In the US, most meningococcal disease in adolescents and young adults is caused by serogroups C, Y and W-135; together, these serogroups account for approximately 80% of IMD cases that occur in Americans between the ages of 11 and 22 years.

Table 1.

There are currently two licensed quadrivalent meningococcal vaccines in Canada and the US, an unconjugated polysaccharide vaccine (Menomune), and a conjugate polysaccharide protein vaccine, MenACWY-DT (Menactra). As is true for other unconjugated polysaccharide vaccines, the unconjugated meningococcal polysaccharide vaccine induces a largely T-cell-independent immunogenic response and therefore does not confer long-lasting immunity in any age group. In contrast, conjugated vaccines induce a T-cell-dependent immunogenic response along with immunologic memory and are believed to confer longer-lasting immunity. Importantly as well, meningococcal conjugate vaccines reduce asymptomatic carriage of N. meningitides which may promote herd immunity.

Early in 2009, NACI updated its recommendations for the choice of meningococcal vaccine for adolescents, such that now, either the meningococcal C conjugate vaccine or the MenACWY-DT quadrivalent vaccine can be used. Choice should be shaped by considering the geographical burden of illness from serogroups A, Y and W135 as well as the age distribution of cases by serogroup. Three provinces—Prince Edward Island, New Brunswick and Ontario—currently offer the MenACWY-DT vaccine for routine immunization. In Ontario, adolescents in Grade 7 receive the vaccine while those in Grade 9 in Prince Edward Island and New Brunswick are immunized.

NACI now also recommends that an adolescent dose of a conjugated meningococcal vaccine be incorporated into the routine vaccination schedule, even if the adolescent has been previously vaccinated as part of a routine infant or 1-year-old meningococcal C vaccination program. According to NACI guidelines, this will help ensure circulating antibody titres against serogroup C, which appear to be important for ongoing protection against IMD.

The optimal age for the adolescent dose is approximately 12 years. Between 1995 and 2006, NACI reported that the incidence of IMD in Canada averaged 0.77 cases per 100,000 population/year, the highest incidence being observed in infants under the age of 12 months, at an incidence rate of 8.7 cases/100,000. This was followed by children between the ages of 1 and 4 where the annual incidence rate was 2.3/100,000.

Novel Quadrivalent Vaccine: Phase III Trial Results

A new quadrivalent meningococcal vaccine has recently been developed that includes cross-reacting material (CRM) of a naturally-occurring non-toxic mutant of diphtheria toxin as the carrier protein. In what was the first direct comparison of the new MenACWY-CRM vaccine to the currently available MenACWY-DT quadrivalent vaccine, a phase III randomized trial in a total of 2170 recipients between 11 and 18 years of age was carried out. Recipients were randomly allocated to one of three lots of the MenACWY-CRM vaccine (n=1631) or to the MenACWY-DT quadrivalent vaccine (n=539). Each subject received a single intramuscular injection in the deltoid muscle.

Blood samples were taken at enrolment and one month following vaccination. The immunogenicity of the two vaccines was compared using human complement (hSBA) for meningococcal serogroups A, C, W-135 and Y. If prevaccination titres were <1:4 (below the limit of detection), seroresponse was defined by seroconversion to a post-vaccination titre of at least 1:8. If the prevaccination titre was at least 1:4, seroresponse was defined by a fourfold or greater increase in titres from before to after vaccination.

Analyses indicated that there were no lot-to-lot inconsistencies between the three lots of the MenACWY-CRM vaccine used in the trial, so responses were compared between those who received any one of the three lots and those who received the MenACWY-DT vaccine. Results showed that the hSBA geometric mean titres (GMTs) one month after vaccination were consistently higher in the MenACWY-CRM vaccine group vs. the MenACWY-DT vaccine group. Indeed, the hSBA GMTs after vaccination with the new vaccine met prespecified criteria for superiority for
able 2).

Table 2.

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Among the prespecified end points, the proportion of vaccine recipients who achieved a post-vaccination hSBA titre of at least 1:8 was analyzed. It was observed that analyses met the criteria for statistical superiority of response to the MenACWY-CRM vaccine compared with response to the MenACWY-DT vaccine for serogroups A, W-135 and Y, while the criteria for non-inferiority were met for serogroup C. The largest difference in the proportion of recipients who achieved a post-vaccination titre of at least 1:8 was seen for serogroup Y disease, where 88% of MenACWY-CRM recipients achieved an hSBA titre of at least this
those who received the MenACWY-DT vaccine (Figure 1).

Figure 1.

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Both vaccines were well tolerated with comparable reactogenicity. Pain was the most common local reaction reported by relatively comparable numbers of adolescents in each group.

Discussion

As discussed in the results from this multicentre, phase III comparator trial, it is still uncertain whether the more robust immunogenic responses seen with the MenACWY-CRM vaccine will translate into improved protection against IMD. Immunogenicity using human complement has been shown in other studies to be a good predictor of vaccine efficacy. Vaccines which have been licensed on the basis of their ability to induce robust immunogenic responses have, in fact, turned out to be effective when used in large-scale vaccination campaigns in many countries, including Canada.

There are other reasons to expect that differences in hSBA responses to the two comparator vaccines might translate into significant clinical differences in vaccinated cohorts as a whole. Other investigators have already shown that when given during the first six months of life, the MenACWY-DT quadrivalent vaccine does not invoke adequate levels of protection against IMD caused by serogroups C, W-135 or Y. In contrast, formulations of the new vaccine, with and without aluminum phosphate adjuvant, were found to be immunogenic in young infants. Importantly, the two vaccines have different carrier proteins—MenACWY-CRM having the Corynebacterium diphtheriae CRM197 protein and the MenACWY-DT vaccine containing diphtheria toxoid carrier protein. Initially, the vaccine used against Haemophilus influenzae type b disease (Hib), which also contained a diphtheria toxoid as the conjugate protein, was found to be effective in one clinical trial but it still had relatively limited immunogenicity in infants under the age of 6 months. A similar lack of efficacy was reported when the same vaccine was given to a cohort of native Alaskan infants.

This was in contrast to results from another trial in which an Hib vaccine using the same CRM conjugate protein as is used in the new vaccine was evaluated in infants, where it was shown to be efficacious. Indeed, since the Hib vaccine using the CRM conjugate protein was introduced in the US, invasive Hib disease has been almost eliminated.

The epidemiology of IMD differs within and between countries. In the US, for example, serogroup Y disease has increased dramatically over the past 20 years and currently accounts for approximately one-third of all IMD.

The significantly greater proportion of recipients who achieved a protective antibody titre against serogroup Y disease following MenACWY-CRM vaccination (81%) compared to those who received the MenACWY-DT vaccine (54%) suggests that protection against serogroup Y disease with the new vaccine is likely to be improved over current incidence rates and could lead to significant reductions in morbidity and mortality attributable to serogroup Y disease.

The clinical trials program evaluating the new vaccine has shown that it is immunogenic in all age groups, including infants as young as 2 months of age and the elderly, and protection against the four serogroups contained in the vaccine persisted out to one year in both children and adolescents.

Our comparative trial indicated that adolescents who received the new MenACWY-CRM vaccine achieved a favourable immunogenic response compared with those who received the MenACWY-DT vaccine. Among recipients of the new vaccine, the percentage of seroresponders to serogroups A, Y and W-135 disease was statistically higher as was the percentage who achieved an hSBA titre of at least 1:8 to serogroups A, Y and W-135. Both vaccines were equally well tolerated with few reported systemic events.

It is, however, important to state that the statistically higher immunogenic responses seen with the new vaccine do not necessarily mean patients are more likely to be protected against serogroups A, C, W-135 and Y disease. While duration of protection may be longer, the higher antibody levels seen initially with the new vaccine may last longer. Ultimately, expert opinion will have to weigh the strength of protection afforded by both vaccines and the regional epidemiology of that disease. When the incidence of serogroup Y disease is substantial—as it is in at least some provinces as well as in the US—the target population is sufficiently at risk to argue in favour of a conjugated quadrivalent vaccine, whether the currently available conjugate vaccine or the new vaccine.

Prevention of IMD from infancy to maturity is a laudable goal. A new vaccine that is capable of eliciting robust immune responses to serogroups responsible for a considerable proportion of disease is highly encouraging.

References:

Jackson LA, Baxter R, Reisinger K, Karsten A, Shah J, Bedell L, Dull PM and the V59P13 Study Group. Phase III comparison of an investigational quadrivalent meningococcal conjugate vaccine with the licensed meningococcal ACWY conjugate vaccine in adolescents. Clinical Infectious Diseases 2009;49(1):e1-10.

National Advisory Committee on Immunization (NACI). Update on the invasive meningococcal disease and meningococcal vaccine conjugate recommendations. Canada Communicable Disease Report April 2009;36:ACS-3.